chr2-96254961-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_017849.4(TMEM127):​c.281G>A​(p.Arg94Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

4
8
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 7.46

Publications

3 publications found
Variant links:
Genes affected
TMEM127 (HGNC:26038): (transmembrane protein 127) This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]
TMEM127 Gene-Disease associations (from GenCC):
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • pheochromocytoma
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • renal cell carcinoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.763
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000499 (73/1461880) while in subpopulation MID AF = 0.00225 (13/5768). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM127NM_017849.4 linkc.281G>A p.Arg94Gln missense_variant Exon 3 of 4 ENST00000258439.8 NP_060319.1 O75204
TMEM127NM_001193304.3 linkc.281G>A p.Arg94Gln missense_variant Exon 3 of 4 NP_001180233.1 O75204
TMEM127NM_001407282.1 linkc.29G>A p.Arg10Gln missense_variant Exon 2 of 3 NP_001394211.1
TMEM127NM_001407283.1 linkc.29G>A p.Arg10Gln missense_variant Exon 2 of 3 NP_001394212.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM127ENST00000258439.8 linkc.281G>A p.Arg94Gln missense_variant Exon 3 of 4 1 NM_017849.4 ENSP00000258439.3 O75204

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000278
AC:
7
AN:
251390
AF XY:
0.0000515
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000499
AC:
73
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.0000426
AC XY:
31
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.0000896
AC:
3
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00225
AC:
13
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000468
AC:
52
AN:
1112008
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
5
10
15
20
25
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41460
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68048
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.445
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 08, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with an abdominal paraganglioma without a family history of PCC/PGL (Alanazi et al., 2020); This variant is associated with the following publications: (PMID: 21156949, 32994724, 31666924) -

Feb 13, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32994724 (2020)), and abdominal paraganglioma (PMID: 31666924 (2019)). The frequency of this variant in the general population, 0.000054 (7/129096 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Pheochromocytoma Uncertain:2Benign:1
Feb 02, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome Uncertain:1
Dec 07, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R94Q variant (also known as c.281G>A), located in coding exon 2 of the TMEM127 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in a Saudi proband with abdominal paraganglioma (Albattal S et al. Oncotarget 2019 Oct;10(57):5919-5931) and also in a patient (also Saudi) undergoing multigene testing for breast cancer (Alanazi M et al. Saudi J Biol Sci 2020 Oct;27(10):2651-2659). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1
Oct 21, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 94 of the TMEM127 protein (p.Arg94Gln). This variant is present in population databases (rs746831347, gnomAD 0.006%). This missense change has been observed in individual(s) with abdominal paraganglioma (PMID: 31666924). ClinVar contains an entry for this variant (Variation ID: 337506). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.038
T;T;.
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;D;D
M_CAP
Benign
0.040
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
1.4
L;L;.
PhyloP100
7.5
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.4
N;N;N
REVEL
Uncertain
0.58
Sift
Benign
0.26
T;T;T
Sift4G
Pathogenic
0.0
D;D;T
Polyphen
0.68
P;P;.
Vest4
0.93
MVP
0.70
MPC
0.48
ClinPred
0.22
T
GERP RS
5.0
Varity_R
0.17
gMVP
0.89
Mutation Taster
=68/32
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs746831347; hg19: chr2-96920699; COSMIC: COSV51497970; API